The European Medicines Agency (EMA) has granted an update to the marketing authorisation for Tyverb® (lapatinib) to be used in combination with Herceptin® (trastuzumab). This combination is indicated for adult patients with breast cancer whose tumours overexpress HER2 (ErbB2) with hormone receptor-negative (HR-) metastatic disease that has progressed on prior trastuzumab therapy(ies) in combination with chemotherapy.1

"We are proud to bring a new chemotherapy-free option to metastatic breast cancer patients. Through vertical dual blockade of the HER2 receptor, the combination of lapatinib and trastuzumab achieves a clinically significant improvement in overall survival for patients with HER2-positive, HR-negative metastatic breast cancer," said Dr Pim Kon, UK Medical Director, GlaxoSmithKline. "We believe this new combination therapy has the potential to make a meaningful impact on the care and survival of women in this breast cancer population."

The combination works by targeting the same HER2 receptor at different points - 'above' and 'below' the cell membrane (vertical) thereby enhancing blockade2 - these agents subsequently produce a vertical dual blockade of the HER2 receptor:

Trastuzumab is a monoclonal antibody that binds to the extracellular ('above') domain of the HER2 receptor.

By targeting both extracellular and intracellular domains of the same receptor [vertical dual HER2 blockade] complementary mechanisms of action may be realised, potentially achieving better pathway inhibition than could be accomplished with either compound alone.2

The EMA approval is based on findings from the EGF104900 study - a randomised, open-label, Phase III study of lapatinib plus trastuzumab versus lapatinib monotherapy in patients with HER2-positive metastatic breast cancer whose disease had progressed on a trastuzumab-containing regimen.3 The primary endpoint of the trial was progression-free survival (PFS), with overall survival (OS) as the secondary endpoint.3

The authorisation for the new indication is based on overall survival (OS) results in the HER2-positive, HR-negative metastatic breast cancer population within the EGF104900 trial. This post-hoc subgroup analysis showed that:1,4

Please note that lapatinib is not licensed for use as a monotherapy in Europe or elsewhere.

Approximately 25% to 30% of women with metastatic breast cancer have tumours which over-express ErbB2, a protein commonly referred to as HER2 (human epidermal growth factor).5 HER2-positive tumours are associated with a worse prognosis and reduced overall survival compared to HER2-negative tumours.5,6 Patients with HER2 advanced or metastatic breast cancer have limited targeted therapy options available to them after trastuzumab-based therapy has failed to halt disease progression.7 GlaxoSmithKline is working with the National Health Service (NHS) to support decision-making about the most appropriate funding route for this new treatment combination of lapatinib and trastuzumab.

Within the EGF104900 trial, the incidence of AEs was similar in both treatment groups (94% vs. 90%). The most frequent adverse reactions (> 25 per cent) in the combination arm were diarrhoea, and nausea. Additional adverse events which affected > 10 per cent of patients who received the combination arm, included rash, fatigue, vomiting, dyspnoea, anorexia and headache. Serious adverse events were experienced by 26 per cent of patients in the combination arm vs. 16% in the monotherapy arm.3,4

Adverse events led to treatment discontinuation in 17 patients (11 per cent) treated with lapatinib plus trastuzumab compared with nine patients (6 per cent) treated with lapatinib monotherapy. In total, six patients had fatal serious adverse events; of these, one - probable but unconfirmed pulmonary embolism in the combination therapy arm - was considered to be related to study treatment. There was an increased incidence of cardiac toxicity, but these events were comparable in nature and severity to those reported from the lapatinib clinical programme. These data are based on exposure to this combination in 149 patients in the pivotal trial.1,3

About Tyverb® (lapatinib)

Lapatinib is an orally administered small molecule that inhibits the tyrosine kinase components of the HER1 (ErbB1 or EGFR) and HER2 (ErbB2) receptors.1 Stimulation of HER1 and HER2 is associated with cell proliferation and with multiple processes involved in tumour progression, invasion, and metastases. Overexpression of these receptors has been reported in a variety of human tumours and is associated with poor prognosis and reduced overall survival compared to HER2-negative tumours.5,6

Lapatinib was first approved for use in combination with capecitabine in the metastatic setting in 2007 (U.S.) and is currently approved in 107 countries including the U.S., Europe, Australia, India, Brazil, Russia, Turkey, South Korea and other countries around the world. Lapatinib plus trastuzumab is not approved for use outside of the EU.

Safety Information

Cardiac toxicity: Lapatinib has been associated with reports of decreases in left ventricular ejection fraction (LVEF). Lapatinib has not been evaluated in patients with symptomatic cardiac failure. Caution should be taken if lapatinib is to be administered to patients with conditions that could impair left ventricular function (including co-administration with potentially cardiotoxic medicinal products). In some cases, LVEF decrease may be severe and lead to cardiac failure. Fatal cases have been reported, causality of the deaths is uncertain. There has been no dedicated study to assess the potential for lapatinib to prolong the QT interval. A small, concentration dependent increase in QTc interval was observed in an uncontrolled, open-label dose escalation study of lapatinib in advanced cancer patients, such that an effect on QT interval cannot be ruled out.1

Interstitial lung disease and pneumonitis: Lapatinib has been associated with reports of pulmonary toxicity including interstitial lung disease and pneumonitis.1Hepatotoxicity: Hepatotoxicity has occurred with lapatinib use and may in rare cases be fatal. The hepatotoxicity may occur days to several months after initiation of treatment.1Diarrhoea: Diarrhoea, including severe diarrhoea, has been reported with lapatinib treatment. Diarrhoea can be potentially life-threatening if accompanied by dehydration, renal insufficiency, neutropenia and/or electrolyte imbalances and fatal cases have been reported.1

Further information on the use of lapatinib in combination with trastuzumab and its safety profile, including routine monitoring and other management requirements, can be found in the Summary of Product Characteristics.1

About Metastatic and HER2-Positive Breast Cancer

Breast cancer is the most common cancer in women worldwide.8 In 2010, nearly 50,000 women in the UK were diagnosed with breast cancer.9 Metastatic breast cancer occurs when the breast cancer cells spread from the first tumour in the breast to other parts of the body.10 Estimates of the number of patients with metastatic breast cancer vary10 but regional UK data suggests that around 5% of patients diagnosed have metastases at the time of diagnosis, with a further 35% developing metastases in the 10 years following diagnosis.11

The prognosis of metastatic breast cancer is often poor; distant metastases are the cause of about 90 per cent of deaths due to breast cancer.12 HER2 positive tumours are associated with a worse prognosis and reduced overall survival compared to HER2-negative tumours.5,6 Clinically, HER2-positive disease often features poorly differentiated, high-grade tumours, lymph node involvement, increased rates of cell proliferation, and a relative resistance to certain types of chemotherapy. As a result, HER2 is an important target for therapy.6

About GlaxoSmithKline

GlaxoSmithKline, one of the world's leading research-based pharmaceutical and healthcare companies - is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For further information please visit www.gsk.com.

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